Biomedical subjects

D M Zimmer

Publications and source records attributed to D M Zimmer.

22 records · Page 2Linked to original sources

PubMed1986

Genotoxicity of the antitumor antibiotic CC-1065.

CC-1065, a very potent antitumor antibiotic, is active against several animal tumors, and against human tumors in the cloning assay at doses 50-1000 times lower than other agents such as adriamycin. It binds and alkylates DNA, and inhibits DNA synthesis, suggesting a potential for genotoxicity. Therefore, the genotoxic effects of CC-1065 were tested in several assay systems. CC-1065 was weakly mutagenic in the Ames Salmonella mutation assay (strain TA100) without S9 activation, but lacked mutagenic activity in TA98 with or without activation. CC-1065 was a very potent mutagen in the Salmonella forward mutation assay (induction of 8-azaguanine resistance), increasing the mutation frequency 19-fold over background at 0.1 ng/ml without activation. In mammalian (V79) cells it was a very potent mutagen without activation, increasing the mutation frequency 20-fold over background a 0.5 ng/ml. CC-1065 induced chromosome aberrations in V79 cells at very low (less than 0.1 ng/ml) doses, making this assay the most sensitive. CC-1065 increased the induction of micronuclei in rats 10- to 20-fold over the background at 200 and 400 micrograms/kg, but not at 100 micrograms/kg. CC-1065 failed to cause DNA breaks or DNA--protein cross-links as measured by the DNA damage/alkaline elution assay.

Animals↗

PubMed1983

Comparative genotoxicity of adriamycin and menogarol, two anthracycline antitumor agents.

Adriamycin and menogarol are anthracyclines which cause more than 100% increase in life span of mice bearing P388 leukemia and B16 melanoma. Unlike Adriamycin, menogarol does not bind strongly to DNA, and it minimally inhibits DNA and RNA synthesis at lethal doses. Adriamycin is a clinically active drug, and menogarol is undergoing preclinical toxicology at National Cancer Institute. In view of the reported mutagenicity of Adriamycin, we have compared the genotoxicity of the two drugs. Our results show that, although Adriamycin and menogarol differ significantly in their bacterial mutagenicity (Ames assay), they have similar genotoxic activity in several mammalian systems. Adriamycin is strongly mutagenic in the Ames assay with TA98 and TA100. Menogarol is nonmutagenic to TA98 and TA100. For the mammalian cell culture systems, V79 (Chinese hamster) cells are exposed for 2 hr to drug, following which cell survival, induction of sister chromatid exchanges, chromosome damage, and production of mutants resistant to 6-thioguanine are measured. The percentage of survival obtained with the two drugs ranges between 25 and 50% at 0.15 microgram/ml and 5 to 15% at 0.3 microgram/ml. At 0.15 microgram/ml, Adriamycin and menogarol increase the percentage of cells with chromosome damage from a background level of 8.8 to 30 and 22.5%, respectively. The same drug concentration causes a small but significant increase in sister chromatid exchange rate. Both drugs are equally active (increase mutation frequency about 3- to 6-fold above background) in producing 6-thioguanine-resistant mutants. The induction of micronuclei in polychromatic erythrocytes of rats is the most sensitive assay system. Both drugs cause 10- to 15-fold increase in micronuclei at nontoxic doses.

Animals↗

PubMed1977

Mammalian host- and fluid-mediated mutagenicity assays of captan and streptozotocin in Salmonella typhimurium.

The mutagenicity of captan and of streptozotocin was tested in vivo by reversion of hisG46 base-pair substitution histidine auxotrophs of Salmonella typhimurium in the peritoneal cavity or in blood, plasma or urine of rats or mice. Genetic response was determined by the frequency of revertants (quantitative test) or by the number of revertants per plate (semiquantitative test). In quantitative HMA captan gave negative results following 3 hourly 500 mg/kg s.c. doses or 1000 mg/kg oral dose in mice with the hisG46 mutant or 2000 mg/kg oral dose in rats with the hisG46, uvrB (TA1950) mutant. The positive control SZN induced many reversions at 0.5 mg/kg i.p. or 10 or 100 mg/kg oral doses. In semiquantitative in vivo blood or urine assays captan gave negative results after a 250 mg/kg oral dose with hisG46. SZN in the same experiment gave positive results in both semiquantitative and quantitative in vivo blood assays following 1000 mg/kg i.p. or 2000 mg/kg oral doses in the rat with TA1950. Rat blood mixed with captan for 45 min before adding TA1950 cells inactivated 1000 mug captan/ml but not 5000 mg/ml in the semiquantitative test. Corresponding figures in the quantitative test were 500 mu/ml and 1000 mug/ml. Rat plasma inactivated the mutagenicity of about 10 times less captan than rat blood. Human blood inactivated about as much captan as rat blood. The mutagenicity of captan was inactivated more efficiently than of SZN by blood. The results of the experiments suggested that captan's mutagenicity is probably inactivated by glutathione of the erythrocytes. Rat S-9 liver microsomal fraction also strongly decreased captan's mutagenicity in a semiquantitative test with the R factor, uvrB, hisG46 (TA100) mutant.

Administration, Oral↗

PubMed1976

Mutagenicity of streptozotocin and several other nitrosourea compounds in Salmonella typhimurium.

The following nitrosourea compounds were compared for their ability to induce mutation (to histidine independence) in the histidine-requiring auxotroph Salmonella typhimurium his G46: MNU, streptozotocin (SZ, streptozocin) and its analogs SZA1 and SZA2, and the antitumor drugs BCNU, CCNU and DCNU. At equitoxic doses SZ, SZA1, SZA2 and MNU were almost equally mutagenic causing 150, 42, 140 and 170 mutants/106 survivors at 20% lethal dose (ID20) ALTHOUGH, ON A WIEGHT BASIS, SZ was the most mutagenic of all the compounds tested. At ID20 BCNU, CCNU and DCNU gave about 0.5 mutants/106 survivors. Our results show that these nitrosoureas, in common with many other drugs (such as cyclophosphamide, daunomycin, etc.) used in cancer chemotherapy, are highly mutagenic. The implication of our results in the screening of drugs for their mutagenicity to man is discussed.

Histidine↗